The nuclear factor κB (NF-κB) family of transcription factors in mammals consists of homo- and hetero-dimeric combinations of five related proteins (p50, p52, p65/RelA, c-Rel, and RelB) that have a marked influence on the expression of numerous genes involved in immunity and inflammation, as well as cellular stress responses, growth, and apoptosis. Diverse pathways activate NF-κB, and control of these pathways is increasingly viewed as an approach to chemotherapy in the many diseases that have an associated inflammatory component, including cancer, stroke, Alzheimer's disease and diabetes.1-10 Activation of NF-κB occurs through multiple pathways. The classical pathway is triggered by binding of pro-inflammatory cytokines (TNFα and IL-1) and of a number of pathogens to several different receptors in the TNF-receptor and Toll-like/IL-1 receptor superfamilies. This leads to recruitment to the plasma membrane and activation of the IκB-kinase complex (IKK) consisting of IKKα and IKKβ kinases, and the scaffold protein NEMO/IKKγ, as well as a number of IKK-associated proteins. The main NFκB that is activated in the classical pathway is the p50/p65 heterodimer that exists in the cytoplasm as a complex with inhibitory protein IκBα. Activation of IKK primarily through IKKβ results in phosphorylation of IκBα on Ser32 and Ser36, followed by polyubiquitination and degradation of IκBα by the 26S proteasome, allowing p50/p65 to translocate to the nucleus.
Release of p50/p65 from IκBα also can be achieved by IKK-independent pathways triggered by DNA damage or oxidative stress that result in phosphorylation of IκBα on Ser residues other than Ser32 or Ser36, again leading to proteosomal degradation of IκBα. This signaling pathway involves a number of kinases including the MAP kinase p38 and casein kinase 2. There is also an oxidative stress pathway that phosphorylates IκBα on Tyr residues, leading to release of p50/p65 without proteosomal degradation of IκBα. Superimposed on the complex activation of p50/p65 is additional downstream regulation of the DNA-binding properties of p50/p65 through phosphorylation, acetylation and peptidyl-prolyl isomerization. Mostly this occurs in p65 and provides multiple points for control of NF-κB activation in a cell-specific and environment-specific manner. A wide range of kinases can phosphorylate p50/p65, which appears essential for the transactivation potential of p50/p65. This includes phosphorylation at many different sites, especially in p65, which adds to the complex regulation of NF-κB.4,10 
There are also alternative pathways to activation of NF-κB that result in formation of homo- or hetero-dimers other than p50/p65. A major alternative pathway, which is independent of IKKβ and NEMO, involves the IKKα homo-dimer whose activation is triggered by cytokines (other than TNFα), ligands such as CD40, and by certain viruses. This pathway requires recruitment of NF-κB-inducing kinase (NIK) with subsequent phosphorylation and activation of the IKKα homodimer. Activated IKKα phosphorylates p100, which is subsequently ubiquitinated and processed by the proteosome to p52. p52 and RelB then form a heterodimer that translocates to the nucleus. As with p50/p65, the p52/RelB heterodimer is further regulated by phosphorylation.4 
A large number of compounds including natural products have been reported to inhibit activation of NF-κB at one or more sites in the complex pathways of activation.11 This includes resveratrol (3,4′,5-trihydroxystilbene, 1), a polyphenolic
phytochemical that is found in numerous foods and is especially abundant in red wine. It has been proposed that the anti-oxidant activity of resveratrol is responsible for the French Paradox;12-14 this relates to the low incidence of cardiovascular disease in a French population with high intake of saturated fat.15 Both trans and cis isomers of resveratrol occur as phytothemicals, and both possess biological activities. Most studies of the biological activities of resveratrol and of synthetic stilbene analogs of resveratrol have focused on trans isomers. Resveratrol has been studied extensively in the context of carcinogenesis as a chemoprevention agent. All three stages of carcinogenesis, i.e., initiation, promotion and progression, have been reported to be inhibited by resveratrol.16 Because resveratrol exhibits anti-oxidant activity, which is based upon its phenolic groups, much of the research on resveratrol and on polyphenolic analogs of resveratrol has focused on anti-oxidant properties.17-21 In addition, the multiple biological activities reported for resveratrol, which in addition to its cardio-protective and anti-carcinogenic activity also includes inhibition of platelet aggregation, modulation of lipoprotein metabolism, anti-inflammatory and vasorelaxing activities,17,22-24 are often ascribed to the anti-oxidant properties of resveratrol. However, the oral bioavailability of resveratrol is low due to rapid metabolism, and the amount of resveratrol in dietary sources such as red wine is low compared to other polyphenols. Consequently, the circulating levels of resveratrol are low suggesting that the direct anti-oxidant effects of resveratrol are unlikely to explain its biological activities.12 Therefore, there has been extensive interest in the ability of resveratrol and other plant polyphenols to affect signaling pathways, including NF-κB.25 Signaling through NF-κB has been shown to be involved in the ability of resveratrol to induce heme oxygenase-1,26 inhibit phorbol ester-induced expression of COX-2,27 inhibit TNFα-induced proliferation of smooth muscle cells,28 enhance the radiosensitivity of lung cancer cells,29 and inhibit nitric oxide and TNFα production by LPS-activated microglia.30 
A model of the overlapping metabolic and inflammatory signaling and sensing pathways in adipocytes and macrophages that influence inflammation is provided by FIG. 2. As shown in FIG. 2, signals from various mediators converge on the inflammatory signaling pathways, including the kinases JNK and IKK. These pathways lead to the production of additional inflammatory mediators such as NF-κB and AP-1 through transcriptional regulation as well as to the direct inhibition of insulin signaling. Opposing the inflammatory pathways are transcriptional factors from the PPAR and LXR families, which promote nutrient transport and metabolism and antagonize inflammatory activity.